The international patent application PCT/EP2009/002798 refers to similar compounds which are inhibitors of receptor tyrosine kinases of the AXL receptor family. These compounds are suitable for the treatment or prevention of disorders associated with, accompanied by or caused by hyperfunction of a receptor of the AXL family. The compounds of PCT/EP2009/002798 are suitable for the treatment of hyperproliferative disorders, such as cancer and particularly cancer metastases.
It is object of the present invention to provide further compounds and pharmaceutically acceptable salts thereof which can be used as pharmaceutically active agents, especially for prophylaxis, treatment and after-treatment of cancer, tumors and particularly cancer metastases.
The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, and the examples of the present application.
The novel quinolinyloxyphenylsulfonamides according to the present invention are represented by the following general formula (I)
wherein—R1 or —R2 represents —O—X—R8;if —R1 represents —O—X—R8 than —R2 represents —H, —OH, —OCH3, —OCF3, —OC2H5, —OC3H7, —OCH2CH2—OCH3, —OCH2CH2—OC2H5;if —R2 represents —O—X—R8 than —R1 represents —H, —OH, —OCH3, —OCF3, —OC2H5, OC3H7, —OCH2CH2—OCH3, —OCH2CH2—OC2H5;—X— represents —CR11R12—, —CR11R12—CR13R14—, —CR11R12—CR13R14—CR15R16—, —CR11R12—CR13R14—CR15R16—CR17R18—, —CR11R12—CR13R14—CR15R16—CR17R18—CR19R20—, —CR11R12—CR13R14—CR15R16—CR17R18—CR19R20—CR21R22—, —(CH2)n—NH—, —CO—, —(CH2)n—CO—, —(CH2)n—NH—CO—NH—, —(CH2)n—NH—CO—, —(CH2)n—NH—CO—O—, —(CH2)n—CO—NH—, —(CH2)n—O—CO—NH—, —(CH2)n—O—CO—, —(CH2)n—O—, —(CH2)n—,n is an integer selected from 1, 2, 3, 4, 5 and 6;—R3, —R4, —R5, —R6 are independently of each other selected from hydrogen, halogen, nitro, C1-6 alkyl, C3-C10-cycloalkyl, C1-6 alkoxy, wherein the C1-6 alkyl, C3-C10-cycloalkyl or C1-6 alkoxy groups are optionally mono- or polysubstituted by hydroxyl, halogen, C1-4 alkyl and/or C1-4 alkoxy, wherein the C1-4 alkyl and/or C1-4 alkoxy groups are optionally mono- or polysubstituted by hydroxyl and/or halogen.—R7 represents(i) a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, C1-6 alkyl, C3-C10-cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C1-6 alkyl, C3-C10-cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,(ii) C1-6 alkyl or C1-6 alkoxy which is unsubstituted or substituted by a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,(iii) a nitrogen atom substituted with a saturated or unsaturated three- to twelve-membered or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,—R8 represents hydrogen, hydroxyl, halogen, C1-6 alkoxy, C1-6 alkylcarbonyl, carboxyl, C3-C10-cycloalkyl, C1-6 alkoxycarbonyl, a heterocyclic group, a heterocycloalkyl group with one or two heteroatoms selected from O, N, S and 2 to 6 carbon atoms, C1-6-alkyl, —NH—CO—NR9R10, —CO—NR9R10, —NR9R10;—R9 and —R10 are independently of each other selected from hydrogen, C3-C6-cycloalkyl, C1-6 alkyl optionally substituted by hydroxyl, halogen and/or C1-4 alkoxy or—R9 and —R10 may combine with the nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by hydroxyl, amino, halogen, —COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 acyloxy, a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system,wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl and/or C1-6 acyloxy groups are optionally substituted by hydroxyl, C1-6 alkoxy, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system;wherein in the amino group one or both hydrogen atoms on said amino group are optionally substituted by C1-6 alkyl or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system, and the C1-6 alkyl group is optionally substituted by hydroxyl, C1-6 alkoxy, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system;wherein the saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system is optionally substituted by hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl groups are optionally substituted by hydroxyl, C1-6 alkoxy, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system; when the carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the carbocyclic or heterocyclic group may be condensed with another saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group to form a bicyclic group.
Preferably —R9 is selected from hydrogen, C1-6-alkyl which is optionally substituted by hydroxyl, halogen and/or C1-4-alkoxy and —R10 is selected from C1-6-alkyl which is optionally substituted by hydroxyl, halogen and/or C1-4-alkoxy.
R11-R22 represent independently of each other linear or branched, substituted or unsubstituted C1-C20-alkyl, —H, —OH, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —OC(CH3)3, —OC4H9, —OPh, —OCH2-Ph, —OCPh3, —SH, —SCH3, —SC2H5, —SC3H7, —S-cyclo-C3H5, —SCH(CH3)2, —SC(CH3)3, —NO2, —F, —Cl, —Br, —I, —N3, —CN, —OCN, —NCO, —SCN, —NCS, —CHO, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COC(CH3)3, —COOH, —COCN, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —OOC—CH3, —OOC—C2H5, —OOC—C3H7, —OOC-cyclo-C3H5, —OOC—CH(CH3)2, —OOC—C(CH3)3, —CONH2, —CONHCH3, —CONHC2H5, —CONHC3H7, —CONH-cyclo-C3H5, —CONH[CH(CH3)2], —CONH[C(CH3)3], —CON(CH3)2, —CON(C2H5)2, —CON(C3H7)2, —CON(cyclo-C3H5)2, —CON[CH(CH3)2]2, —CON[C(CH3)3]2, —NH2, —NHCH3, —NHC2H5, —NHC3H7, —NH-cyclo-C3H5, —NHCH(CH3)2, —NHC(CH3)3, —N(CH3)2, —N(C2H5)2, —N(C3H7)2, —N(cyclo-C3H5)2, —N[CH(CH3)2]2, —N[C(CH3)3]2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SOC(CH3)3, —SO2CH3, —SO2C2H5, —SO2C3H7, —SO2-cyclo-C3H5, —SO2CH(CH3)2, —SO2C(CH3)3, —SO3H, —SO3CH3, —OCHF2, —SO3C2H5, —SO3C3H7, —SO3-cyclo-C3H5, —SO3CH(CH3)2, —SO3C(CH3)3, —OCF3, —OC2F5, —O—COOCH3, —O—COOC2H5, —O—COOC3H7, —O—COO-cyclo-C3H5, —O—COOCH(CH3)2, —O—COOC(CH3)3, —NH—CO—NH2, —NH—CO—NHCH3, —NH—CO—NHC2H5, —NH—CO—NHC3H7, —NH—CO—NH-cyclo-C3H5, —NH—CO—NH[CH(CH3)2], —NH—CO—NH[C(CH3)3], —NH—CO—N(CH3)2, —NH—CO—N(C2H5)2, —NH—CO—N(C3H7)2, —NH—CO—N(cyclo-C3H5)2, —NH—CO—N[CH(CH3)2]2, —NH—CO—N[C(CH3)3]2, —NH—CS—NH2, —NH—CS—NH-cyclo-C3H5, —NH—CS—NHC3H7, —NH—CS—NH[CH(CH3)2], —NH—CS—NH[C(CH3)3], —NH—CS—N(CH3)2, —NH—CS—N(C2H5)2, —NH—CS—N(C3H7)2, —NH—CS—N(cyclo-C3H5)2, —NH—CS—N[CH(CH3)2]2, —NH—CS—N[C(CH3)3]2, —NH—C(═NH)—NH2, —NH—C(═NH)—NHCH3, —NH—C(═NH)—NHC2H5, —NH—CS—NHC2H5, —NH—C(═NH)—NHC3H7, —NH—C(═NH)—NH-cyclo-C3H5, —NH—C(═NH)—NH[CH(CH3)2], —NH—C(═NH)—NH[C(CH3)3], —NH—CS—NHCH3, —NH—C(═NH)—N(CH3)2, —NH—C(═NH)—N(C2H5)2, —NH—C(═NH)—N(C3H7)2, —NH—C(═NH)—N(cyclo-C3H5)2, —NH—C(═NH)—N[CH(CH3)2]2, —NH—C(═NH)—N[C(CH3)3]2, —O—CO—NH2, —O—CO—NHCH3, —O—CO—NHC2H5, —O—CO—NHC3H7, —O—CO—NH-cyclo-C3H5, —O—CO—NH[CH(CH3)2], —O—CO—NH[C(CH3)3], —O—CO—N(CH3)2, —O—CO—N(C2H5)2, —O—CO—N(C3H7)2, —O—CO—N(cyclo-C3H5)2, —O—CO—N[CH(CH3)2]2, —O—CO—N[C(CH3)3]2, —O—CO—OCH3, —O—CO—OC2H5, —O—CO—OC3H7, —O—CO—O-cyclo-C3H5, —O—CO—OCH(CH3)2, —O—CO—OC(CH3)3, —CH2F—CHF2, —CF3, —CH2Cl, —CHCl2, —CCl3, —CH2Br—CHBr2, —CBr3, —CH2I—CHI2, —Cl3, —CH2—CH2F—CH2—CHF2, —CH2—CF3, —CH2—CH2Cl, —CH2—CHCl2, —CH2—CCl3, —CH2—CH2Br—CH2—CHBr2, —CH2—CBr3, —CH2—CH2I, —CH2—CHI2, —CH2—Cl3, —CH3, —C2H5, —C3H7, -cyclo-C3H5, —CH(CH3)2, —C(CH3)3, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, -Ph, —CH2-Ph, —CPh3, —CH═CH2, —CH2—CH═CH2, —C(CH3)═CH2, —CH═CH—CH3, —C2H4—CH═CH2, —CH═C(CH3)2, —C≡CH, —C≡C—CH3, —CH2—C≡CH, —Si(CH3)3, and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts thereof.
As used herein, the term “C1-6 alkyl” or “linear or branched C1-C6-alkyl” refers to —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —CH(CH3)—C3H7, —CH2—CH(CH3)—C2H5, —CH(CH3)—CH(CH3)2, —C5H11, —C(CH3)2—C2H5, —CH2—C(CH3)3, —CH(C2H5)2, —C2H4—CH(CH3)2, —C6H13, —C3H6—CH(CH3)2, —C2H4—CH(CH3)—C2H5, —CH(CH3)—C4H9, —CH2—CH(CH3)—C3H7, —CH(CH3)—CH2—CH(CH3)2, —CH(CH3)—CH(CH3)—C2H5, —CH2—CH(CH3)—CH(CH3)2, —CH2—C(CH3)2—C2H5, —C(CH3)2—C3H7, —C(CH3)2—CH(CH3)2, —C2H4—C(CH3)3, and —CH(CH3)—C(CH3)3, wherein in the afore-mentioned groups one or more hydrogen atoms can be replaced by —OH, —OCH3, —OC2H5, —SH, —SCH3, —SC2H5, —NO2, —F, —Cl, —Br, —I, —N3, —COCH3, —COC2H5, —COOCH3, —COOC2H5, —OOC—CH3, —OOC—C2H5, —COOH, —CONH2, —CON(CH3)2, —CON(C2H5)2, —NH2, —NHCH3, —NHC2H5, —N(CH3)2, —N(C2H5)2, —SOCH3, —SOC2H5, —SO3H, —OCF3, —CF3, —C≡CH. Preferred are —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, and —C5H11. Especially preferred are —CH3, —C2H5, —C3H7.
As used herein, the term “C3-C10-cycloalkyl” or “carbocyclic group” refers to

Preferred are the following cycloalkyls:

As used herein, the term “C2-6 alkenyl” or “linear or branched C2-C6-alkenyl” refers to —CH═CH2, —CH2—CH═CH2, —CH═CH—CH3, —C2H4—CH═CH2, —CH═CH—C2H6, —CH2—C(CH3)═CH2, —CH(CH3)—CH═CH, —CH═C(CH3)2, —C(CH3)═CH—CH3, —CH═CH—CH═CH2, —C3H6—CH═CH2, —C2H4—CH═CH—CH3, —CH2—CH═CH—C2H5, —CH═CH—C3H7, —CH2—CH═CH—CH═CH2, —CH═CH—CH═CH—CH3, —CH═CH—CH2—CH═CH2, —C(CH3)═CH—CH═CH2, —CH═C(CH3)—CH═CH2, —CH═CH—C(CH3)═CH2, —C2H4—C(CH3)═CH2, —CH2—CH(CH3)—CH═CH2, —CH(CH3)—CH2—CH═CH2, —CH2—CH═C(CH3)2, —CH2—C(CH3)═CH—CH3, —CH(CH3)—CH═CH—CH3, —CH═CH—CH(CH3)2, —CH═C(CH3)—C2H5, —C(CH3)═CH—C2H5, —C(CH3)═C(CH3)2, —C(CH3)2—CH═CH2, —CH(CH3)—C(CH3)═CH2, —C(CH3)═CH—CH═CH2, —CH═C(CH3)—CH═CH2, —CH═CH—C(CH3)═CH2, —C4H8—CH═CH2, —C3H6—CH═CH—CH3, —C2H4—CH═CH—C2H5, —CH2—CH═CH—C3H7, —CH═CH—C4H9, —C3H6—C(CH3)═CH2, —C2H4—CH(CH3)—CH═CH2, —CH2—CH(CH3)—CH2—CH═CH2, —CH2—CH═CH—CH3, —CH(CH3)—C2H4—CH═CH2, —C2H4—CH═C(CH3)2, —C2H4—C(CH3)═CH—CH3, —CH2—CH(CH3)—CH═CH—CH3, —CH(CH3)—CH2—CH═CH—CH3, —C(CH3)═CH2, —CH2—CH═CH—CH(CH3)2, —CH2—CH═C(CH3)—C2H6, —CH2—C(CH3)═CH—C2H5, —CH(CH3)—CH═CH—C2H5, —CH═CH—CH2—CH(CH3)2, —CH═CH—CH(CH3)—C2H5, —CH═C(CH3)—C3H7, —C(CH3)═CH—C3H7, —CH2—CH(CH3)—C(CH3)═CH2, —CH(CH3)—CH2—C(CH3)═CH2, —CH(CH3)—CH(CH3)—CH═CH2, —CH2—C(CH3)2—CH═CH2, —C(CH3)2—CH2—CH═CH2, —CH2—C(CH3)═C(CH3)2, —CH(CH3)—CH═C(CH3)2, —C(CH3)2—CH═CH—CH3, —CH(CH3)—C(CH3)═CH—CH3, —CH═C(CH3)—CH(CH3)2, —C(CH3)═CH—CH(CH3)2, —C(CH3)═C(CH3)—C2H5, —C(CH3)2—C(CH3)═CH2, —CH(C2H5)—C(CH3)═CH2, —C(CH3)(C2H5)—CH═CH2, —CH(CH3)—C(C2H5)═CH2, —CH2—C(C2H5)═CH—CH3, —C[CH2—CH(CH3)2]═CH2, —C2H4—CH═CH—CH═CH2, —CH2—CH═CH—CH2—CH═CH2, —CH═CH—C2H4—CH═CH2, —CH═CH—C(CH3)3, —CH2—CH═CH—CH═CH—CH3, —CH═CH—CH2—CH═CH—CH3, —C[CH(CH3)(C2H5)]═CH2, —CH═CH—CH═CH—C2H5, —CH2—CH═CH—C(CH3)═CH2, —C(C2H5)═CH—C2H5, —CH2—CH═C(CH3)—CH═CH2, —CH2—C(CH3)═CH—CH═CH2, —C(C2H5)═C(CH3)2, —CH(CH3)—CH═CH—CH═CH2, —CH═CH—CH2—C(CH3)═CH2, —C(C4H9)═CH2, —CH═CH—CH(CH3)—CH═CH2, —CH═C(CH3)—CH2—CH═CH2, —C[C(CH3)3]═CH2, —CH═C(CH3)—CH═CH—CH3, —C(CH3)═CH—CH2—CH═CH2, —CH(C2H5)—CH═CH—CH3, —CH═CH—C(CH3)═CH—CH3, —CH═CH—CH═C(CH3)2, —C(C3H7)═CH—CH3, —C(CH3)═CH—CH═CH—CH3, —CH═C(CH3)—C(CH3)═CH2, —CH2—C(C3H7)═CH2, —C(CH3)═CH—C(CH3)═CH2, —C(CH3)═C(CH3)—CH═CH2, and —CH═CH—CH═CH—CH═CH2.
Preferred are —CH═CH2, —CH2—CH═CH2, —C(CH3)═CH2, —CH═CH—CH3, —C2H4—CH═CH2, —CH2—CH═CH—CH3. Especially preferred are —CH═CH2—CH2—CH═CH2.
As used herein, the term “C2-6 alkynyl” or “linear or branched C2-C6-alkynyl” refers to —C≡CH, —C≡C—CH3, —CH2—C≡CH, —C2H4—C≡CH, —CH2—C≡C—CH3, —C≡C—C2H5, —C3H6—C≡CH, —C2H4—C≡C—CH3, —CH2—C═C—C2H6, —C═C—C3H7, —CH(CH3)—C≡CH, —CH2—CH(CH3)—C≡CH, —CH(CH3)—CH2—C≡CH, —CH(CH3)—C≡C—CH3, —C4H8—C≡CH, —C3H6—C≡C—CH3, —C2H4—C≡C—C2H5, —CH2—C≡C—C3H7, —C2H4—CH(CH3)—C≡CH, —CH2—CH(CH3)—CH2—C≡CH, —CH(CH3)—C2H4—C≡CH, —CH2—CH(CH3)—C≡C—CH3, —CH(CH3)—CH2—C≡C—CH3, —CH(CH3)—C≡C—C2H5, —CH2—C≡C—CH(CH3)2, —C≡C—CH(CH3)—C2H5, —C≡C—CH2—CH(CH3)2, —C≡C—C4H9, —C≡C—C(CH3)3, —CH(C2H5)—C≡C—CH3, —C(CH3)2—C≡C—CH3, —CH(C2H5)—CH2—C≡CH, —CH2—CH(C2H5)—C≡CH, —C(CH3)2—CH2—C≡CH, —CH2—C(CH3)2—C≡CH, —CH(CH3)—CH(CH3)—C≡CH, —CH(C3H7)—C≡CH, —C(CH3)(C2H5)—C≡CH, —C≡C—C≡CH, —CH2—C≡C—C≡CH, —C≡C—C≡C—CH3, —CH(C≡CH)2, —C2H4—C≡C—C≡CH, —CH2—C═C—CH2—C≡CH, —C≡C—C2H4—C≡CH, —CH2—C≡C—C≡C—CH3, —C≡C—CH2—C≡C—CH3, —C≡C—C≡C—C2H5, —C≡C—CH(CH3)—C≡CH, —CH(CH3)—C≡C—C≡CH, —CH(C≡CH)—CH2—C≡CH, —C(C≡CH)2—CH3, —CH2—CH(C≡CH)2, —CH(C≡CH)—C≡C—CH3. Preferred are —C≡CH and —C≡C—CH3.
As used herein, the term “aryl” or “carbocyclic group” refers to phenyl, indenyl, indanyl, naphthyl, 1,2-dihydro-naphthyl, 2,3-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl(tetralinyl), fluorenyl, anthryl(anthracenyl), 9,10-dihydroanthryl, 1,2,3,4-tetrahydro-anthryl, 1,2,3,4,5,6,7,8-octahydro-anthryl, azulenyl, diphenyl methyl, benzyl, triphenylmethyl(trityl), styryl, naphthoquinonyl, acenaphthyl, anthraquinonyl, phenanthryl(phenanthrenyl) and especially to a mono- or bicyclic 6 to 10 membered ring system, preferably phenyl or napthyl.
As used herein, the term “heteroaryl” or “heterocyclic ring” or “heterocyclic group” refers to heteroaromatic groups which have from 5 to 10 ring atoms, from 1 to 4 of which are selected from O, N and/or S. Preferred groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono and bicyclic ring systems are included. Typical heteroaryl groups which are at least partially aromatic include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, indolizinyl, indolyl, isoindolyl, benzo[b]furyl, thiophenyl, benzo[b]thienyl, indazolyl, benzimidazolyl, benzthiazolyl, thiazolyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, tetrahydroquinolyl, benzooxazolyl, chrom-2-onyl, indazolyl, indenyl. Said herteroaryl groups may further be substituted by one, two, three, four, five or more substituents selected from the group consisting of R18-R30, linear or branched C1-C6-alkyl, C3-C6-cycloalkyl, linear or branched C2-C6-alkenyl, linear or branched C2-C6-alkynyl and aryl.
Preferred heterocyclic groups from which also R7 can be selected are:

R7 can also be selected from the above-mentioned heterocyclic groups. In addition R7 can also stand for the following residue:
wherein R23 to R27 are independently of each other selected from the substituents mentioned below.
Preferred heterocyclic —NR9R10 groups are:

Said preferred herteroaryl groups and heterocyclic groups may further be substituted by one, two, three, four, five or more substituents selected from the group consisting of R23—R35, linear or branched C1-C6-alkyl, C3-C10-cycloalkyl, linear or branched C2-C6-alkenyl, linear or branched C2-C6-alkynyl and aryl.
As used herein, the term “heterocyclic group” or “heterocyclic ring” or “heterocyclic ring system” or “heterocyclyl” refers to carbocycles having at least one heteroatom in the ring such as oxygen, nitrogen, or sulfur. Such heterocycles may be saturated or partially unsaturated but not aromatic. Examples for heterocyclic residues are 1,3-dioxolane, benzo[1,3]dioxolyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl, pyrrolinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl.
Aryl refers to phenyl, substituted phenyl and heteroaryl, wherein substituted phenyl and heteroaryl have the meanings as defined above.
As used herein, the term “C1-C6 alkyloxy” or “C1-C6 alkoxy” refers to the residue —O—C1-C6-alkyl, wherein C1-C6-alkyl has the meanings as defined above. The following C1-C6 alkoxy groups are preferred —O—CH3, —O—C2H5, —O—C3H7, —O—CH(CH3)2, —O—C4H9, —O—CH2—CH2—CH(CH3)2, —O—CH(CH3)—C2H5, —O—C(CH3)3, and —O—C5H11. Most preferred are —O—CH3, —O—C2H5 and —O—C3H.
As used herein, the term “C1-C6 alkyloxycarbonyl” or “C1-C6 alkoxycarbonyl” refers to the residue —CO—O—C1-C6-alkyl, wherein C1-C6-alkyl has the meanings as defined above. Preferred C1-C6 alkoxycarbonyl groups are —CO—OCH3, —CO—OC2H5, —CO—OC3H7, —CO—OCH(CH3)2, —CO—OC4H9, —CO—OCH2—CH(CH3)2, —CO—OCH(CH3)—C2H5, —CO—OC(CH3)3, and —CO—OC5H11. Most preferred are —CO—OCH3, —CO—OC2H5, —CO—OC3H7.
As used herein, the term “C1-C6 alkylcarbonyl” or “C1-C6 alkanoyl” or “C1-C6 acyl” refers to the residue —CO—C1-C6-alkyl, wherein C1-C6-alkyl has the meanings as defined above. Preferred C1-C6 acyl groups are —CO—CH3, —CO—C2H5, —CO—C3H7, —CO—CH(CH3)2, —CO—C4H9, —CO—CH2—CH(CH3)2, —CO—CH(CH3)—C2H5, —CO—C(CH3)3, and —CO—C5H11. Most preferred are —CO—CH3, —CO—C2H5, —CO—C3H7.
As used herein, the term “C1-C6 alkylcarbonyloxy” or “C1-C6 alkanoyloxy” or “C1-C6 acyloxy” refers to the residue —O—CO—C1-C6-alkyl, wherein C1-C6-alkyl has the meanings as defined above. Preferred C1-C6 acyloxy groups are —O—CO—CH3, —O—CO—C2H5, —O—CO—C3H7, —O—CO—CH(CH3)2, —O—CO—C4H9, —O—CO—CH2—CH(CH3)2, —O—CO—CH(CH3)—C2H5, —O—CO—C(CH3)3, and —O—CO—C5H11. Most preferred are —O—CO—CH3, —O—CO—C2H5, —O—CO—C3H7.
The term “substituted” or “substituted alkyl”, “substituted cycloalkyl”, “substituted heterocyclyl”, “substituted aryl”, “substituted heteroaryl”, “substituted heterocyclic group”, “substituted carbobicyclic group” respectively shall refer to the addressed residue such as “alkyl”, “cycloalkyl”, “heterocyclyl”, “aryl”, or “heteroaryl” bearing one, two, three, four, five or more, preferably one or two substituents R23 to R35 independently selected from the following group:

—OH, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —OC(CH3)3, —OC4H9, —OPh, —OCH2-Ph, —OCPh3, —SH, —SCH3, —SC2H5, —SC3H7, —S-cyclo-C3H5, —SCH(CH3)2, —SC(CH3)3, —NO2, —F, —Cl, —Br, —I, —N3, —CN, —OCN, —NCO, —SCN, —NCS, —CHO, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COC(CH3)3, —COOH, —COCN, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —OOC—CH3, —OOC—C2H5, —OOC—C3H7, —OOC-cyclo-C3H5, —OOC—CH(CH3)2, —OOC—C(CH3)3, —OCHF2, —CONH2, —CONHCH3, —CONHC2H5, —CONHC3H7, —CONH-cyclo-C3H5, —CONH[CH(CH3)2], —CONH[C(CH3)3], —CON(CH3)2, —CON(C2H5)2, —CON(C3H7)2, —CON(cyclo-C3H5)2, —CON[CH(CH3)2]2, —CON[C(CH3)3]2, —NH2, —NHCH3, —NHC2H5, —NHC3H7, —NH-cyclo-C3H5, —NHCH(CH3)2, —NHC(CH3)3, —N(CH3)2, —N(C2H5)2, —N(C3H7)2, —N(cyclo-C3H5)2, —N[CH(CH3)2]2, —N[C(CH3)3]2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SOC(CH3)3, —SO2CH3, —SO2C2H5, —SO2C3H7, —SO2-cyclo-C3H5, —SO2CH(CH3)2, —SO2C(CH3)3, —SO3H, —SO3CH3, —SO3C2H5, —SO3C3H7, —SO3-Cyclo-C3H5, —SO3CH(CH3)2, —SO3C(CH3)3, —OCF3, —OC2F5, —O—COOCH3, —O—COOC2H5, —O—COOC3H7, —O—COO-cyclo-C3H5, —O—COOCH(CH3)2, —O—COOC(CH3)3, —NH—CO—NH2, —NH—CO—NHCH3, —Si(CH3)3, —NH—CO—NHC2H5, —NH—CO—NHC3H7, —NH—CO—NH-cyclo-C3H5, —O—CO—NH2, —O—CO—NHCH3, —O—CO—NHC2H5, —O—CO—NHC3H7, —O—CO—NH-cyclo-C3H5, —O—CO—NH[CH(CH3)2], —O—CO—NH[C(CH3)3], —O—CO—N(CH3)2, —O—CO—N(C2H5)2, —O—CO—N(C3H7)2, —O—CO—N(cyclo-C3H5)2, —O—CO—N[CH(CH3)2]2, —O—CO—N[C(CH3)3]2, —O—CO—OCH3, —O—CO—OC2H5, —O—CO—OC3H7, —O—CO—O-cyclo-C3H5, —O—CO—OCH(CH3)2, —O—CO—OC(CH3)3, —CH2F—CHF2, —CF3, —CH2Cl, —CHCl2, —CCl3, —CH2Br—CHBr2, —CBr3, —CH21—CHI2, —Cl3, —CH2—CH2F—CH2—CHF2, —CH2—CF3, —CH2—CH2Cl, —CH2—CHCl2, —CH2—CCl3, —CH2—CH2Br—CH2—CHBr2, —CH2—CBr3, —CH2—CH2I, —CH2—CHI2, —CH2—Cl3, -cyclo-C3H5, -Ph, —CH2-Ph, —CPh3, —CH═CH2, —CH2—CH═CH2, —C(CH3)═CH2, —CH═CH—CH3, —C2H4—CH═CH2, —CH═C(CH3)2, —C≡CH, —C≡C—CH3, —CH2—C≡CH, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —CH(CH3)—C3H7, —CH2—CH(CH3)—C2H5, —CH(CH3)—CH(CH3)2, —5H11, —C(CH3)2—C2H5, —CH2—C(CH3)3, —CH(C2H5)2, —C2H4—CH(CH3)2, —C6H13, —C3H6—CH(CH3)2, —C2H4—CH(CH3)—C2H5, —CH(CH3)—C4H9, —CH2—CH(CH3)—C3H7, —CH(CH3)—CH2—CH(CH3)2, —CH(CH3)—CH(CH3)—C2H5, —CH2—CH(CH3)—CH(CH3)2, —CH2—C(CH3)2—C2H5, —C(CH3)2—C3H7, —C(CH3)2—CH(CH3)2, —C2H4—C(CH3)3, and —CH(CH3)—C(CH3)3.
Preferred residues R8—X—O— are selected from:
whereinthe substituent —R13 has the meanings as defined herein;the substituent —R22 refers to the residues disclosed above and preferably to phenyl, benzyl, C1-C6-alkyl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, —OH, —CH2—OH, —C2H4—OH, —OCH3, —CH2—OCH3 or —C2H4—OCH3.
Further preferred compounds of the present invention are such compounds wherein R8—X—O— is selected from:
whereinthe substituents —R9, —R10, —R13 and C1-C6-alkyl have the meanings as defined herein.
Another group of preferred compounds has residues R8—X—O— selected from the following groups:
whereinthe substituent —R13 has the meanings as defined above.
Preferred are also compounds of the general formula (I)
whereinone of —R1 and —R2 represents —O—X—R8; and the other one of —R1 and —R2 represents —H, —OH, —OCH3, —OCF3, —OC2H5, —OC3H7, —OCH2CH2—OCH3, —OCH2CH2—OC2H5;
—X— represents —CR11R12—, —CR11R12—CR13R14—, —CR11R12—CR13R14—CR15R16—, —CR11R12—CR13R14—CR15R16—CR17R18—, —CR11R12—CR13R14—CR15R16—CR17R18—CR19R20—, —(CH2)n—NH—, —CO—, —(CH2)n—CO—, —(CH2)n—NH—CO—NH—, —(CH2)n—NH—CO—, —(CH2)n—NH—CO—O—, —(CH2)n—CO—NR9—, —(CH2)n—O—CO—NH—, —(CH2)n—O—CO—, —(CH2)n—O—, —(CH2)n—;
n is an integer selected from 1, 2, 3, 4, 5 and 6;
—R3, —R4, —R5, —R6 are independently of each other selected from —H, halogen, nitro, C1-4-alkyl, C3-C5-cycloalkyl, C1-6-alkoxy;
—R8 represents —H, —OH, —F, —Cl, —Br, —I, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —OC(CH3)3, —OC4H9, —CHO, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COC(CH3)3, —COOH, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —CONH2, —CONHCH3, —CONHC2H5, —CONHC3H7, —CONH-cyclo-C3H5, —CONH[CH(CH3)2], —CONH[C(CH3)3], —CON(CH3)2, —CON(C2H5)2, —CON(C3H7)2, —CON(cyclo-C3H5)2, —CON[CH(CH3)2]2, —CON[C(CH3)3]2, —NH2, —NHCH3, —NHC2H5, —NHC3H7, —NH-cyclo-C3H5, —NHCH(CH3)2, —NHC(CH3)3, —N(CH3)2, —N(C2H5)2, —N(C3H7)2, —N(cyclo-C3H5)2, —N[CH(CH3)2]2, —N[C(CH3)3]2, —OOC—CH3, —OOC—C2H5, —OOC—C3H7, —OOC-cyclo-C3H5, —OOC—CH(CH3)2, —OOC—C(CH3)3, —NH—CO—NH2, —NH—CO—NHCH3, —NH—CO—NHC2H5, —NH—CO—NHC3H7, —NH—CO—NH-cyclo-C3H5, —NH—CO—NH[CH(CH3)2], —NH—CO—NH[C(CH3)3], —NH—CO—N(CH3)2, —NH—CO—N(C2H5)2, —NH—CO—N(C3H7)2, —NH—CO—N(cyclo-C3H5)2, —NH—CO—N[CH(CH3)2]2, —NH—CO—N[C(CH3)3]2, —NH—COOCH3, —NH—COOC2H5, —NH—COOC3H7, —NH—COO-cyclo-C3H5, —NH—COOCH(CH3)2, —NH—COOC(CH3)3, —O—CO—NH2, —O—CO—NHCH3, —O—CO—NHC2H5, —O—CO—NHC3H7, —O—CO—NH-cyclo-C3H5, —O—CO—NH[CH(CH3)2], —O—CO—NH[C(CH3)3], —O—CO—N(CH3)2, —O—CO—N(C2H5)2, —O—CO—N(C3H7)2, —O—CO—N(cyclo-C3H5)2, —O—CO—N[CH(CH3)2]2, —O—CO—N[C(CH3)3]2, —NH—CO—NR9R10, —CO—NR9R10, —NR9R10, —CH2F—CHF2, —CF3, —CH2Br, —CH2—CH2F, —CH2—CH2Cl, —CH2—CH2Br, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C(CH3)3, —C4H9, —C5H11, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, -Ph, —CH2-Ph, —CH═CH2, —CH2—CH═CH2, —C≡CH,
—R9 and —R19 are independently of each other selected from —H, —CH2F—CHF2, —CF3, —CH2Cl, —CH2Br, —CH2—CH2F, —CH2—CH2Cl, —CH2—CH2Br, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C(CH3)3, —C4H9, —O5H11, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11;—R7 represents one of the following groups —CH3, —C2H5, —C3H7,

R11— R27 represent independently of each other —H, —OH, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —OC(CH3)3, —OC4H9, —OCH2Ph, —OPh, —SH, —SCH3, —SC2H5, —NO2, —F, —Cl, —Br, —I, —CN, —CHO, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COON, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —OOC—CH3, —OOC—C2H5, —OOC—C3H7, —OOC-cyclo-C3H5, —OOC—CH(CH3)2, —CONH2, —CONHCH3, —CONHC2H5, —CONHC3H7, —CONH-cyclo-C3H5, —CONH[CH(CH3)2], —CON(CH3)2, —CON(C2H5)2, —CON(C3H7)2, —CON(cyclo-C3H5)2, —NH—OC—CH3, —NH—OC—C2H5, —NH—OC—C3H7, —NH—OC-cyclo-C3H5, —NH—OC—CH(CH3)2, —NH—OC—C(CH3)3, —NH2, —NHCH3, —NHC2H5, —NHC3H7, —NH-cyclo-C3H5, —NHCH(CH3)2, —N(CH3)2, —N(C2H5)2, —N(C3H7)2, —N(cyclo-C3H5)2, —N[CH(CH3)2]2, —SOCH3, —SOC2H5, —SO2CH3, —SO2C2H5, —SO3H, —SO3CH3, —SO3C2H5, —SO3C3H7, —OCF3, —OC2F5, —OCH2F—OCHF2, —CH2F—CHF2, —CF3, —CH2Cl, —CH2Br, —CH2—CH2F, —CH2—CH2Cl, —CH3, —C2H5, —C3H7, -cyclo-C3H5, —CH(CH3)2, —C(CH3)3, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —CH═CH2, —CH2—CH═CH2, —CH═CH—CH3, —C≡CH, —C≡C—CH3, —CH2—C≡CH, -Ph, —CH2-Ph, —CH═CH-Ph;
and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts thereof.
If —R1 is —O—X—R8, —R2 is preferably —H, —OCH3, —OCF3, —OC2H5 and if —R2 is —O—X—R8, than —R1 is preferably —H, —OCH3, —OCF3, —OC2H5.
Preferably —R3, —R4, —R5, —R6 are independently of each —OCH3, —OC2H5, —OC3H7, —OCF3, —F, —Cl, —Br, —I, —CH3, —C2H5, —C3H7, -cyclo-C3H5, —CH(CH3)2, and more preferably —OCH3, —OC2H5, —OCF3, —F, —Cl, —Br, —CH3, —C2H5. Moreover it is preferred if at least one of —R3, —R4 and —R5 are selected from —F or —Cl. It is also preferred if at least one of —R3 and —R4 is —F and preferably —R3 is —F.
Preferably —R7 is one of the following groups —CH3, —C2H5, —C3H7, —C4H9, —C5H11,
—R8 represents preferably

Compounds wherein R1 and R2 are a methoxy group are excluded from the present application. Such compounds having the substitution pattern of the compounds disclosed herein have shown moderate to low activity or no activity and are consequently not preferred. Also compounds of general formula (I), wherein both groups R1 and R2 are ethoxy groups are still not preferred and could also be excluded from the present invention. However compounds wherein both of R1 and R2 represent propoxy, butoxy, pentoxy etc. have shown activity and belong to the compounds of the present invention and are consequently not excluded from the scope of protection.
Excluded from this application and excluded from the patent claims and excluded from the general formula (I) are the following compounds which are excluded by the following disclaimer:    N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-methyl-N-(2-phenylethyl)sulfamide,    N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-1-phenylmethanesulfonamide,    N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-2-phenylethanesulfonamide,    N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-phenylpropane-1-sulfonamide.
The following specific compounds are also preferred which are selected from the group comprising or consisting of:    1) 2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    2) 2-Fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    3) 4-Chloro-2-fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    4) N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethyl-benzenesulfonamide,    5) N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-trifluoromethyl-benzenesulfonamide,    6) 2,6-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    7) N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-nitro-benzenesulfonamide,    8) Biphenyl-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-loxy]-phenyl}-amide,    9) 3-Difluoromethoxy-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    10) N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenoxy-benzenesulfonamide,    11) 2,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    12) 2,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    13) Biphenyl-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    14) N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-phenoxy-benzenesulfonamide,    15) 2-Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    16) 2,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    17) 2,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    18) 4-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-methoxy-benzenesulfonamide,    19) 2-Bromo-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    20) 2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    21) N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-nitro-benzenesulfonamide,    22) 3-Fluoro-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    23) 3-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    24) N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,    25) N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide,    26) 2-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    27) 4-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    28) N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methyl-benzenesulfonamide,    29) 2-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    30) 3-Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    31) Thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)amide,    32) 2,6-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    33) N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide,    34) 3,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-methoxy-benzenesulfonamide,    35) 3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide.    36) N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    37) 3-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    38) 2-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    39) ′N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-trifluoromethyl-benzenesulfonamide    40) N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-nitro-benzenesulfonamide    41) 3-Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    42) N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-methoxy-benzenesulfonamide,    43) 3-Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    44) N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methyl-benzenesulfonamide,    45) N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide,    46) N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-trifluoromethoxy-benzenesulfonamide,    47) 2,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    48) 3,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    49) 2,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    50) 2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin)-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    51) 2,6-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    52) 3,4-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    53) 3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    54) 3-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    55) 2-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-5-methyl-benzenesulfonamide,    56) 3-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-4-methyl-benzenesulfonamide,    57) 3-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    58) Naphthalene-1-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    59) N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-phenoxy-benzenesulfonamide,    60) Cyclopropanesulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    61) 1-Methyl-1H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    62) 5-Methyl-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    63) 5-Chloro-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    64) 2,4-Dichloro-thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    65) Thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    66) 3-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester,    67) Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    68) 1-Ethyl-1H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    69) 3-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    70) N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-methyl-benzenesulfonamide,    71) N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide,    72) 3-Cyano-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    73) 2-Phenyl-ethenesulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    74) Quinoline-8-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,    75) 3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide,    76) 3,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-methoxy-benzenesulfonamide,    77) 2,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    78) N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethoxy-benzenesulfonamide,    79) Butane-1-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide,    80) 2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(piperidin-3-ylmethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    81) 2-Fluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    82) 2,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    83) 2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    84) 2,5-Difluoro-N-{3-fluoro-4-[7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,    85) N-(3-Fluoro-4-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,    86) N-(3-Fluoro-4-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy}-quinolin-4-yloxy]-phenyl)-2-trifluoromethyl-benzenesulfonamide,    87) N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,    88) N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide,    89) N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-2-trifluoromethyl-benzenesulfonamide,    90) 2,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,    91) N-{4-[6,7-Bis-(2-methoxy-ethoxy)-quinolin-4-yloxy]-3-fluoro-phenyl}-2,6-difluoro-benzenesulfonamide,    92) {4-[2-Fluoro-4-(2-fluoro-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-acetic acid ethyl ester,    93) 2-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-N,N-dimethyl-acetamide,    94) Cyclohexanecarboxylic acid 4-[4-(2,5-difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yl ester,    95) N-(3-Fluoro-4-{6-methoxy-7-[3-(tetrahydro-pyran-4-ylamino)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,    96) N-{4-[7-(3-Cyclopropylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,    97) N-{4-[7-(3-Cyclobutylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,    98) N-(4-{7-[3-(3-tert-Butyl-ureido)-propoxy]-6-methoxy-quinolin-4-yloxy}-3-fluoro-phenyl)-2-trifluoromethyl-benzenesulfonamide,    99) N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,    100) N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,    101) N-{-4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,    102) N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide.    103) N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-2-methoxy-benzenesulfonamide    104) 2,6-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide    105) Thiophene-2-sulfonic acid {3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-amide    106) 2,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide    107) 1-Methyl-1H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-amide    108) 2-Chloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide    109) N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-2-nitro-benzenesulfonamide    110) 2,6-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    111) N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-fluoro-benzenesulfonamide    112) N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,5-difluoro-benzenesulfonamide    113) Benzo[b]thiophene-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide    114) Benzo[b]thiophene-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide    115) Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-loxy}-phenyl)-amide    116) Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    117) Benzo[b]thiophene-3-sulfonic acid (3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    118) N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide    119) 2,6-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    120) (3-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-carbamic acid tert-butyl ester    121) (3-{4-[4-(2,5-Difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-carbamic acid tert-butyl ester    122) N-{4-[7-(3-Amino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2,5-difluoro-benzenesulfonamide hydrochloride    123) 2,5-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    124) 2,5-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    125) 2,6-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    126) N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide    127) 2,5-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    128) 2,6-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    129) Thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    130) 5-Chloro-thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    131) 5-Methyl-thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    132) N-[5-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-4-methyl-thiazol-2-yl]-acetamide    133) Thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    134) 2,5-Dichloro-thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    135) 3-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester    136) Benzo[b]thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    137) Furan-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    138) 3,5-Dimethyl-isoxazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    139) 1-Methyl-1H-pyrazole-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    140) 1-Ethyl-1H-pyrazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    141) 2-Methyl-1H-imidazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    142) Cyclopropanesulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    143) 2-Phenyl-ethenesulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    144) Thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    145) 5-Chloro-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    146) 2,4-Dichloro-thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    147) Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    148) Furan-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    149) 2-Methyl-1H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    150) 1-Methyl-1H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)amide    151) 2,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    152) 2,6-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    153) N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide    154) 2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    155) 3-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenylsulfamoyl}-thiophene-2-carboxylic acid methyl ester    156) 3-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester    157) 3-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenylsulfamoyl}-thiophene-2-carboxylic acid methyl ester    158) 3-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester    159) 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide    160) 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    161) 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid (3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl)-amide    162) 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    163) 1-Methyl-1H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide    164) 1-Methyl-1H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    165) 1-Methyl-1H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide    166) 1-Methyl-1H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    167) 2-Methyl-3H-imidazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide    168) 2-Methyl-3H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    169) 2-Methyl-3H-imidazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide    170) 2-Methyl-3H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide    171) 2,5-Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide    172) 2,6-Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide    173) 2,6-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    174) N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-2-trifluoromethoxy-benzenesulfonamide    175) 2,5-Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide    176) 2,6-Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide    177) N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2,5-difluoro-benzenesulfonamide    178) N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2,6-difluoro-benzenesulfonamide    179) N-{-4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethoxy-benzenesulfonamide    180) 2,5-Dichloro-N-{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-benzenesulfonamide    181) 2,6-Dichloro-N-{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-benzenesulfonamide    182) 5-Chloro-thiophene-2-sulfonic acid {4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-amide    183) N-(5-{-4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenylsulfamoyl}-4-methyl-thiazol-2-yl)-acetamide    184) 3-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenylsulfamoyl}-thiophene-2-carboxylic acid methyl ester    185) Furan-2-sulfonic acid {-4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-amide    186) Thiophene-2-sulfonic acid {4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-amide    187) 2,5-Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    188) 2,6-Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    189) N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide    190) N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide    191) 2,5-Dichloro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    192) 2,6-Dichloro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    193) N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,5-difluoro-benzenesulfonamide    194) N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide    195) N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide    196) N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide    197) 2,5-Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    198) 2,6-Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    199) 2,5-Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-benzenesulfonamide    200) 2,6-Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-benzenesulfonamide    201) N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethyl-benzenesulfonamide    202) N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethoxy-benzenesulfonamide    203) 2,5-Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-benzenesulfonamide    204) 2,6-Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-benzenesulfonamide    205) Naphthalene-2-sulfonic acid [3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-amide    206) Cyclopropanesulfonic acid [3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-amide    207) 2,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide    208) N-(3-Methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide    209) N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide    210) N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide    211) Acetic acid 4-{4-[4-(2,5-difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-butyl ester    212) Acetic acid 4-{4-[2-fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-butyl ester    213) N-{2-Fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethyl-benzenesulfonamide    214) N-{3-Fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethyl-benzenesulfonamide    215) N-(2-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
The present invention also comprises pharmaceutically acceptable salts of the compounds according to the general formula (I), all stereoisomeric forms of the compounds according to the general formula (I) as well as solvates, especially hydrates or prodrugs thereof. A prodrug is commonly described as an inactive or protected derivative of an active ingredient or a drug, which is converted to the active ingredient or drug in the body.
In case, the inventive compounds bear basic and/or acidic substituents, they may form salts with organic or inorganic acids or bases. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphtholsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. Examples for suitable inorganic or organic bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.
Some of the compounds of the present invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
Certain compounds of the general formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. Where a compound according to the general formula (I) contains an alkene moiety, the alkene can be presented as a cis or trans isomer or a mixture thereof. When an isomeric form of a compound of the invention is provided substantially free of other isomers, it will preferably contain less than 5% w/w, more preferably less than 2% w/w and especially less than 1% w/w of the other isomers.
Another aspect of the present invention relates to the use of the inventive quinolinyloxyphenylsulfonamide derivatives as drugs, i.d. as pharmaceutically active agents applicable in medicine.
The inventive quinolinyloxyphenylsulfonamides are useful for the treatment and/or prevention of AXL receptor tyrosine kinase induced disorders, wherein the AXL receptor tyrosine kinase induced disorders are selected from the group comprising hyperproliferative disorders, breast, colon, prostate, lung, gastric, ovarian, endometrial, renal, hepatocellular, thyroid, uterine cancer, esophageal carcinoma, squamous cell carcinoma, leukemia, osteosarcoma, melanoma, glioblastoma, and neuroblastoma.
Moreover the inventive quinolinyloxyphenylsulfonamides are useful for the preparation of a pharmaceutical formulation for prophylaxis, treatment and after-treatment cancer, tumors and cancer metastases. Thus, the quinolinyloxyphenylsulfonamide compounds of the present invention can be used for prophylaxis and treatment of various cancer types and especially of cancer metastases.
Furthermore, the compounds of the present invention are useful for the treatment and after-treatment of various cancer types such as adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, breast cancer, Burkitt's lymphoma, corpus cancer, CUP-syndrome (carcinoma of unknown primary), colorectal cancer, small intestine cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose and throat tumors, hematologic neoplasias, hairy cell leukemia, urethral cancer, skin cancer, skin testis cancer, brain tumors (gliomas), brain metastases, testicle cancer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer in the mouth area and on lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymph node cancer (Hodgkin's/Non-Hodgkin's), lymphomas, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's disease, mycosis fungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, non-Hodgkin's lymphomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer, plasmocytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, Schneeberger disease, esophageal cancer, spinalioms, T-cell lymphoma (mycosis fungoides), thymoma, tube carcinoma, eye tumors, urethral cancer, urologic tumors, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, Wilm's tumor, cervical carcinoma and tongue cancer.
Most active are the inventive compounds on lung cancer, lymph node cancer (Hodgkin's/Non-Hodgkin's), head and neck tumors (tumors of the ear, nose and throat area), breast cancer, ovarian cancer, gastric cancer, gastrointestinal tumors, intestinal tumors.
Another aspect of the present invention is directed to the use of at least one quinolinyloxyphenylsulfonamide compound and/or pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical formulation for prophylaxis, treatment and/or after-treatment of cancer, tumors and especially cancer metastases.
Still another aspect of the present invention is directed to pharmaceutical compositions comprising at least one quinolinyloxyphenylsulfonamide compound of the present invention as active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents. The pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluent and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way. The preferred preparations are adapted for oral application. These administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, powders and deposits.
Furthermore, the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain at least one compound according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient.
The pharmaceutical compositions according to the present invention containing at least one compound according to the present invention, and/or a pharmaceutical acceptable salt thereof as active ingredient will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, extrudates, deposits, gels, elixirs, dispersable granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable carrier, preferably with an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules) and the like. Moreover, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the tablet or capsule. Powders and tablets may contain about 5 to about 95 weight % of the quinolinyloxyphenylsulfonamide compound and/or the respective pharmaceutically active salt as active ingredient.
Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among suitable lubricants there may be mentioned boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Suitable disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents as well as preservatives may also be included, where appropriate. The disintegrants, diluents, lubricants, binders etc. are discussed in more detail below.
Moreover, the pharmaceutical compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimise the therapeutic effect(s), e.g. antihistaminic activity and the like. Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
Liquid form preparations include solutions, suspensions, and emulsions. As an example, there may be mentioned water or water/propylene glycol solutions for parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be present in combination with a pharmaceutically acceptable carrier such as an inert, compressed gas, e.g. nitrogen. For preparing suppositories, a low melting fat or wax, such as a mixture of fatty acid glycerides like cocoa butter is melted first, and the active ingredient is then dispersed homogeneously therein e.g. by stirring. The molten, homogeneous mixture is then poured into conveniently sized moulds, allowed to cool, and thereby solidified.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.
The compounds according to the present invention may also be delivered transdermally. The transdermal compositions may have the form of a cream, a lotion, an aerosol and/or an emulsion and may be included in a transdermal patch of the matrix or reservoir type as is known in the art for this purpose.
The term capsule as recited herein refers to a specific container or enclosure made e.g. of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredient(s). Capsules with hard shells are typically made of blended of relatively high gel strength gelatins from bones or pork skin. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and/or preservatives. Under tablet a compressed or moulded solid dosage form is understood which comprises the active ingredients with suitable diluents. The tablet may be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation, or by compaction well known to a person of ordinary skill in the art.
Oral gels refer to the active ingredients dispersed or solubilised in a hydrophilic semi-solid matrix. Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended e.g. in water or in juice.
Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 5 to about 95% by weight of the total composition, preferably from about 25 to about 75 weight %, and more preferably from about 30 to about 60 weight %.
The term disintegrants refers to materials added to the composition to support break apart (disintegrate) and release the pharmaceutically active ingredients of a medicament. Suitable disintegrants include starches, “cold water soluble” modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscarmellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures. The amount of disintegrant in the composition may range from about 2 to about 20 weight % of the composition, more preferably from about 5 to about 10 weight %.
Binders are substances which bind or “glue” together powder particles and make them cohesive by forming granules, thus serving as the “adhesive” in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat corn rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2 to about 20 weight % of the composition, preferably from about 3 to about 10 weight %, and more preferably from about 3 to about 6 weight %.
Lubricants refer to a class of substances which are added to the dosage form to enable the tablet granules etc. after being compressed to release from the mould or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine. Lubricants are usually added at the very last step before compression, since they must be present at the surface of the granules. The amount of lubricant in the composition may range from about 0.2 to about 5 weight % of the composition, preferably from about 0.5 to about 2 weight %, and more preferably from about 0.3 to about 1.5 weight % of the composition.
Glidents are materials that prevent caking of the components of the pharmaceutical composition and improve the flow characteristics of granulate so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition may range from about 0.1 to about 5 weight % of the final composition, preferably from about 0.5 to about 2 weight %.
Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent may vary from about 0.1 to about 5 weight % of the composition, preferably from about 0.1 to about 1 weight %.